Argatroban monohydrate is a synthetic derivative of L-arginine having an anticoagulant activity in that it directly and reversibly inhibits thrombin or the formation thereof.
The preparation of Argatroban monohydrate starting from (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid is described in WO2009124906.
EP0008746 describes how to obtain Argatroban starting from (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid, wherein the peptide coupling is obtained through the formation of an anhydride mixed with isobutyl chloroformate.
Also EP0823430 describes how to obtain Argatroban starting from (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid and performs the peptide coupling in presence of phosphoryl chloride.
Obtaining 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidine carboxylic acid starting from N-nitro-arginine was described in U.S. Pat. No. 4,201,863. U.S. Pat. No. 4,201,863 reacts protected N-nitro arginine such as Boc anhydride with isobutyl chloroformate, so as to obtain a mixed anhydride which is then reacted with 4-methyl-2-piperidine carboxylic ethyl ester acid to obtain 2-piperidine carboxylic acid, 1-[2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methyl-ethyl ester, hydrochloride as a mixture of diastereoisomers.
The resolution of the pipecolic intermediate, used in the synthesis processes described above, is indicated in JP2212473 wherein racemic ethyl 4-methylpiperidine-2-carboxylate is exposed to L-tartaric acid in aprotic polar solvent or in the same solvent mixed with an alcohol so as to form the diastereomeric salt of (2R,4R)-4-methylpiperidine-2-carboxylate with L-tartaric acid, which is subjected to precipitation and purification. The removal of L-tartaric acid leads to the desired compound. Following the resolution procedure as described in JP2212473, the purity of the isolated products is extremely variable and the process reveals poor yields.
Thus, there strongly arises the need for a synthetic process which leads to obtaining the ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate intermediate, which is essential in the processes described for the synthesis of Argatroban, in a rapid manner, reducing costs, with high yields and capable of preventing the resolution of the pipecolic intermediate and possibly limiting or excluding highly toxic substances, such as for example alkyl chloroformates.